1. Field of the Invention
The present invention relates generally to the prevention of dental caries, peridontitis, gingivitis and pyorrhoea alveolaris and more particularly to an inhibitor of dental plaque formation which is an etiologic factor in these diseases.
2. Description of Prior Art
Among diseases of the mouth, both dental caries and pyorrhoea alveolaris are major disorders which may lead to a premature loss of teeth and are encountered with high frequency in dental practice. It has by now been well established in the field of dentistry that these diseases are caused by the indiginous bacteria in the oral cavity and, regarding the mechanism of onset, that the presence of a dental plaque is essential. Thus, the sucrose contained in food is transformed into insoluble polysaccharides (hereinafter referred to collectively as insoluble glucan) by glycosyl transferase (hereinafter referred to as GTase), an enzyme extracellularly secreted by Streptococcus mutans which is a member of the oral bacterial flora, and as the insoluble glucan is deposited on the surface of the tooth, a dental plaque is formed as a conglomerate of bacterial cells including those of S. mutans. Here, the bacterial cells account for about 70 percent of the dental plaque, the figure found by subtracting the combined amount of said insoluble glucan and food residues from the total amount of dental plaque, and as these bacteria metabolize the carbohydrates in food by their glycolytic systems, organic acids such as lactic acid are produced to lower the pH of the dental plaque. When the surface pH of the tooth drops to 5.4 or less, the tooth enamel undergoes decalcification. This is the mechanism of onset and progression of caries. On the other hand, the toxins and other substances elaborated by the bacteria growing in the dental plaque as well as the dead cells irritate the gingiva to cause peridontitis, gingivitis and even pyorrhoea alveolaris.
Since the existence of a dental plaque is, thus, essential to the onset of the two major diseases of the mouth, i.e. carries and pyorrhoea alveolaris, it is believed that these diseases could be effectively prevented if the dental plaque be somehow removed or its formation be forestalled. Along this line of thinking, various approaches have been proposed in recent years. Taking the removal of dental plaque as an example, enzymes for decomposing the insoluble glucan have been disclosed in Japanese Patent Publication No. 38113/1977 (an insoluble glucan-dissolving enzyme derived from a bacterial strain belonging to the genus Flavobacterium), Japanese Patent Publication No. 1070/1981 (an insoluble glucan-decomposing enzyme derived from a strain of the genus Pseudomonas) and Japanese Patent Publication No. 12274/1984 (an .alpha.-1,3-glycosidic bond-cleaving enzyme derived from a strain belonging to the genus Streptomyces), for instance. An enzyme system discharging the dual function of removing dental plaques and destroying bacteria has been disclosed in Japanese Patent Publication No. 21603/1983 (a combination of dextranase with a bacterial cell wall-lysing enzyme). For the prevention of dental plaque formation, several substances showing specific antibacterial activity against S. mutans have been disclosed in Japanese laid-open Patent Application KOKAI No. 63-119416/1988 (gymnemic acids) and Japanese Patent Publication No. 26083/1988 (triterpene compounds). On the other hand, as suggested in Japanese Patent Publication No. 24488/1988 and Japanese laid-open Patent Application KOKAI 63-277612/1988, attempts have been made to block the process of formation of a dental plaque, i.e. agglomeration of oral bacteria to form a bacterial mass, by inhibiting the very production of insoluble glucan by S. mutans.
Despite the above assiduous research toward removal or prevention of a dental plaque, there is no universally accepted dental plaque remover or inhibitor that is fully effective and fully satisfactory, and there has been a standing demand for the development of a powerful dental plaque remover or inhibitor substance.
Inspired by the thought that if the GTase of Streptococcus mutans could be directly inhibited in the stage of its transformation of sucrose to insoluble glucan, the production of insoluble glucan would be effectively prevented to suppress formation of a dental plaque with very high efficiency, the inventor of the present invention isolated and partially purified said enzyme from cultures of S. mutans and using the crude enzyme, screened a large number of substances in respect of GTase inhibitory activity, as well as the intensity of such activity. Surprisingly, the inventor discovered that several compounds of the following general formula (I) ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 may be the same or different and each represents a hydrogen atom or a methyl group or a pharmaceutically acceptable salt thereof have potent GTase-inhibitory activity and that they completely inhibit the adhesion of Streptococcus mutans to the surface of an human tooth in a culture system favorable to the production of said insoluble glucan. The present invention has been accomplished on the basis of the above findings.